A growing body of evidence indicates that the biological activity of HMGB1 is critically determined by its redox state. This study demonstrates that metastatic cancer cells actively maintain HMGB1 in its fully reduced form (red-HMGB1), enabling the formation of the CXCL12/HMGB1 heterocomplex, a signaling unit that potentiates CXCR4-dependent migration and invasion.
Mechanistically, tumor cells were found to release HMGB1 together with components of the thioredoxin (Trx)/thioredoxin reductase (TrxR) redox system into the extracellular environment. This observation is particularly relevant because the chemotactic activity of HMGB1 requires the all-thiol reduced isoform. Oxidation of these cysteine residues prevents the formation and activity of the CXCL12/HMGB1 heterocomplex.
Cancer metastasis and HMGB1 redox regulation
The study further reveals that highly metastatic cancer cells possessing a functional Trx/TrxR axis respond robustly to the CXCL12/HMGB1 heterocomplex, exhibiting enhanced directional migration and invasiveness through CXCR4 activation. In contrast, less aggressive tumor cells lacking detectable thioredoxin reductase expression fail to sustain extracellular red-HMGB1. These cells rapidly internalize CXCL12 and show limited responsiveness to the heterocomplex, suggesting that redox regulation directly influences metastatic behavior.
From a translational perspective, targeting the CXCL12/HMGB1 heterocomplex, inhibiting thioredoxin-dependent HMGB1 reduction, or disrupting CXCR4 engagement may represent complementary strategies to suppress tumor invasion and metastatic dissemination.
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